Aging is a major risk factor for both the development of primary tuberculosis (TB) disease and for the conversion of latent Mycobacterium tuberculosis (M.tb) infection to active TB disease. As a consequence, persons over the age of 65 have the highest TB case rate and are the most susceptible to TB associated death. The immunological factors that contribute to the increased susceptibility of the elderly to TB remain largely unknown. The overarching hypothesis of this program project is that specific changes in inflammatory pathways (termed inflammaging) mediate unique and sub-optimal re-programming in pulmonary and systemic immunity during aging, and worsen the outcome of M.tb infection in the elderly. Project 1 will analyze how pulmonary surfactant and complement contribute to the loss of alveolar complexity within the aging lung and modify the initial cellular interaction with M.tb. Project 2 will address age-associated changes in the function of alveolar macrophages and how they affect M.tb infection. Project 3 will determine the impact of aging and inflammaging on control of primary and latent M.tb infection in old mice. Project 4 will investigat M.tb specific monocyte and T cell function in elderly subjects with latent or active TB. Altogether, these studies will provide mechanistic information to understand how inflammaging and immune senescence impact M.tb infection in the elderly. The program brings together an established group of collaborative scientists with expertise in clinical TB, TB pathogenesis and the immune response to infection, the latter both in human and animal models.